In addition to KRAS exon 2 mutations, other RAS mutations in tumor samples predict a poor response to antiepidermal growth factor receptor agents such as panitumumab among patients with metastatic colon cancer, according to a report published online Sept. 12 in the New England Journal of Medicine.
In a secondary and exploratory analysis of data from a phase-III randomized clinical trial, patients whose tumors carried any activating RAS mutations did not benefit from, and may have been harmed by, combined panitumumab plus FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) chemotherapy, said Dr. Jean-Yves Douillard of the Institut de Cancerologie de l’Ouest Rene Gauducheau, Nantes (France), and his associates.
Dr. Jean-Yves Douillard
In contrast, patients whose tumors did not carry any activating RAS mutations had clear improvements in progression-free and overall survival when they received the combination panitumumab plus FOLFOX4 treatment.
If these findings are confirmed in other studies, they indicate that "further refinement of tumor-specific genetic markers will allow more accurate selection of patients who are likely to have a response to a particular treatment and prevent toxic effects in those who are unlikely to benefit," the researchers said.
At present, oncologists only test for KRAS exon 2 mutations to identify patients least likely to respond to antiepidermal growth factor receptor (anti-EGFR) therapy. However, even with this effort at patient selection, there remains "a substantial fraction" of patients who have no KRAS exon 2 mutations but still do not benefit from the treatment.
Dr. Douillard and his colleagues reasoned that perhaps the presence of activating mutations in KRAS or NRAS genes might further rule out patients who won’t respond to anti-EGFR agents. So they studied activating mutations of the RAS oncogene family using data from the PRIME (Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study, which compared the efficacy and safety of FOLFOX4 alone against that of FOLFOX4 plus panitumumab in metastatic colon cancer.
Their industry-sponsored secondary analysis involved 1,060 study subjects in whom RAS status could be ascertained: 512 patients whose banked tumor specimens had no RAS mutations and 548 whose tumors had any RAS mutations in exons 2, 3, or 4.
In the patients with no RAS mutations, progression-free survival was longer with the combination therapy (10.1 months) than with FOLFOX alone (7.9 months), as was overall survival (26.0 vs 20.2 months, respectively).
In contrast, among patients who didn’t have KRAS mutations in exon 2 but did have activating mutations in other RAS genes, progression-free survival was significantly shorter with the combined panitumumab-FOLFOX4 therapy (7.3 months) than with FOLFOX4 alone (8.8 months). Overall survival also was shorter.
These trends were observed across all subgroups of patients and for all meaningful endpoints, the investigators said (N. Engl. J. Med. 2013 Sept. 12;369:1023-34 [doi:10.1056/NEJMoa1305272]).
"The observed incidence, types, and severity of adverse events associated with panitumumab-FOLFOX4 in the nonmutated RAS and mutated RAS subgroups were similar to the previously reported safety findings in PRIME, and no new safety signals were identified," Dr. Douillard and his associates said.
These findings must be confirmed in further studies such as pooled trials or meta-analyses of anti-EGFR therapy, they added.
This study was supported by the Royal Marsden Hospital, the Institute of Cancer Research, the National Institute for Health Research, and the Biomedical Research Centre, all in the United Kingdom; Amgen; and Oncologia Ca Granda Onlus Foundazione in Milan. Amgen supervised the gene sequencing analysis, performed all statistical analyses, and assisted with manuscript preparation. Dr. Douillard and his associates reported ties to numerous industry sources.